tbuckley/cabot-search huggingface dataset:
Abstract 5860: Five-year survival of patients with late stage prostate cancer: Comparison of the military health system with the US general population
Authors: Jie Lin, Darryl Nousome, Jiji Jiang, Gregory Chesnut, Craig Shriver, Kangmin Zhu
Journal: Cancer Research (2022)

Abstract While the five-year survival for local and regional prostate cancer is nearly 100%, it decreases dramatically for advanced (stages III and IV) prostate cancer. Access to health care is an important factor that affects cancer prognosis. The Military Health System (MHS) provides universal health care to beneficiaries. However, it is unclear whether the universal care translates into improved survival among patients with advanced prostate cancer. We compared survival of patients with advanced prostate cancer between the MHS and the U.S. general population. The MHS patients (N= 5,379) were identified from the Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR). Patients in the U.S. general population (N=21,516) were identified from the Surveillance, Epidemiology, and End Results (SEER) program. All patients were diagnosed between January 1, 1987 and December 31, 2013. The two populations were matched on age (within 5 years), race, and diagnosis year. Multivariable Cox regression hazard model was used to estimate hazard ratios (HRs) for ACTUR compared to SEER. ACTUR patients exhibited longer 5-year survival than matched SEER patients (HR=0.74, 95% CI=0.67-0.83), after adjustment for the potential confounders. In stratified analysis, the improved survival was observed for ages 50 years or older, both white and black races, all tumor stages, and grades. In stratified analysis by treatment receipt, the improved survival of ACTUR patients compared to SEER patients remained regardless of the receipt of surgery or radiation treatment. Our results suggested that MHS beneficiaries with advanced prostate cancer had longer survival than their counterparts in the U.S. general population. Universal health care in the MHS might translate into improved survival for advanced prostate cancer. Disclaimers: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions, or policies of the USUHS, HJF, the DoD or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Jie Lin, Darryl Nousome, Jiji Jiang, Gregory Chesnut, Craig Shriver, Kangmin Zhu. Five-year survival of patients with late stage prostate cancer: Comparison of the military health system with the US general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5860.
Abstract 840: PMEPA1 is an oncogene linked to TGF-β signaling in hepatocellular carcinoma
Authors: Marta Piqué-Gili, Carmen Andreu-Oller, Roser Pinyol, Marina Bárcena-Varela, Roger Esteban-Fabró, Judit Peix, Jordi Abril-Fornaguera, Katherine E. Lindblad, Miguel Torres-Martin, Daniela Sia, Amaia Lujambio, Josep M. Llovet
Journal: Cancer Research (2022)

Abstract Background: Transforming growth factor β (TGFβ) has a dual role in cancer, including hepatocellular carcinoma (HCC). It acts as a tumor suppressor in early stages of hepatocarcinogenesis, but promotes epithelial-to-mesenchymal transition, angiogenesis and immunosuppression in advanced stages. PMEPA1 (prostate transmembrane protein androgen induced 1), a direct target gene of the TGFβ pathway that negatively regulates TGFβ signaling by interacting with SMAD proteins, has been shown to promote TGFβ oncogenic effects in other cancers and we decided to explore its role in HCC pathogenesis. Methods: We analyzed transcriptomic, genomic, epigenomic and clinicopathological data of a discovery cohort of 228 HCCs and a validation cohort of 361 HCCs. PMEPA1 levels were quantified by qPCR in the discovery cohort. PMEPA1 overexpression was validated in 6 independent cohorts (n = 916) using microarray and RNAseq data. Genetically engineered mouse models were generated through hydrodynamic tail-vein injection. Equal amounts of plasmids overexpressing PMEPA1, TGFB1 and MYC were injected in mice to evaluate survival. Molecular and histopathological analyses of the murine tumors are currently ongoing. Results: PMEPA1 was overexpressed in 18% of human HCCs [FC &amp;gt; 2; n = 203/1144], a feature associated with TGFβ signaling (p &amp;lt; 0.05). Overexpression of PMEPA1 was associated with gene body hypermethylation (p &amp;lt; 0.0001). HCCs displaying both TGFβ signaling and high PMEPA1 levels (11% of cases) were significantly enriched in signatures of immune exhaustion, late TGFβ activation, TME response to TGFβ and active stroma (p &amp;lt; 0.05) compared to HCCs with TGFβ signalling alone (8% of cases) or PMEPA1 high levels alone (11% of cases). In vivo, overexpression of MYC+PMEPA1 led to HCC development in 9/16 mice and showed a lower survival when compared to the control arm, overexpression of MYC alone (p = 0.014). On the contrary, only 1/12 mice in the MYC+PMEPA1+TGFβ1 condition developed HCC and none of the MYC+TGFβ1 mice. Conclusion: PMEPA1 upregulation is linked to TGF-β activation and an aggressive phenotype in human HCC. Overexpression PMEPA1 in combination with MYC in vivo led to HCC development, showing for the first time the oncogenic role of PMEPA1 in this cancer. Citation Format: Marta Piqué-Gili, Carmen Andreu-Oller, Roser Pinyol, Marina Bárcena-Varela, Roger Esteban-Fabró, Judit Peix, Jordi Abril-Fornaguera, Katherine E. Lindblad, Miguel Torres-Martin, Daniela Sia, Amaia Lujambio, Josep M. Llovet. PMEPA1 is an oncogene linked to TGF-β signaling in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 840.
Abstract 6243: RAR gamma interactome and cistrome guide the androgen receptor enhancer usage in prosate cancer
Authors: Sajad A. Wani, Jaimie S. Gray, Moray J. Campbell
Journal: Cancer Research (2022)

Abstract Epigenetic mechanisms in prostate cancer (PCa) alter androgen receptor (AR) enhancer access resulting in re-wired AR signaling and cancer progression and/or therapy resistance. Previously, we established miR-96 targets RARγ and its coactivator TACC1, which in turn impacts AR signaling associated with PCa progression. In the current study we sought to define the RARγ complex, its interactions with the AR, and in turn how this controls gene expression. Increased RARγ levels through miR-96 treatments increased both ENZA antiproliferative sensitivity associated with an increase in G1 and G2/M. IMPACT-seq identified miR-96 recognition elements (MREs) in HPr1AR (~1950 at 24h) and LNCaP cells (~ 350) with ~ 150 shared. In parallel, m6A-Seq revealed that the epitranscriptome mark m6A differed significantly between cells. For example, m6A was more significantly enriched on TACC1 mRNA in LNCaP compared to HPr1AR and m6A-marked MRE resulted in genes being more signficantly down-regulated by miR96, including TACC1. RIME revealed that RARγ significantly interacts miR-96 differentially expressed transcripts (DETs) and proteins (DEPs) including m6A regulators (METTL3) and QSER1 complex that protects against enhancer methylation. Reflecting this, restoring RARγ levels in 22Rv1 cells, increased AR genomic binding 12-fold to greater than 9,500 sites and further by TACC1. These gained AR sites were enriched for GATA and Homeobox motifs, significantly overlapped with H3K27ac and super-enhancers, and also ChromHMM-defined Poised Enhancers (logPV = 163) and Transcribed regions (logPV = 179). RNA-Seq experiments revealed that RARγ/TACC1 significantly altered the frequency and fold change of DHT-regulated genes. Finally, miR-96 antagomir/ENZA treatments drove a unique transcriptome that triggered cell cycle arrest and significantly associated with worse survival in the SU2C cohort. To summarize these data suggest that miR-96 is directed to control the RARγ/TACC1 complex in part by m6A marks. Restoring the RARγ/TACC1 complex increased association with potential bookmarking factor like QSER1 and redirects AR to active enhancers that promote ENA-regulated genes and increase propensity for cells to undergo cell arrest. Citation Format: Sajad A. Wani, Jaimie S. Gray, Moray J. Campbell. RAR gamma interactome and cistrome guide the androgen receptor enhancer usage in prosate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6243.
Abstract 297: Prophylaxis and treatment of metastatic breast cancer and melanoma using S100A9-targeted cowpea mosaic virus nanoparticles
Authors: Young Hun Chung, Jooneon Park, Hui Cai, Nicole F. Steinmetz
Journal: Cancer Research (2022)

Abstract The current study investigates the use of an immunostimulatory plant virus nanoparticle called the cowpea mosaic virus (CPMV) in both the prophylaxis and treatment of metastatic breast cancer and melanoma. Metastatic cancer remains to this day one of the most difficult areas in oncology to treat and diagnose. Current standardized treatments consist of systemically administered chemotherapeutics, which are not targeted to the diseased areas and oftentimes cause significant side effects. Therefore, novel treatments such as targeted immunotherapies are under development. The S100A9 protein is upregulated in the tumor microenvironment and it plays an important role in tumor metastasis, aggressiveness, and tumor immunosuppression. It is present not only in the pre-metastatic tumor environment, but is also heavily secreted and expressed after metastatic tumor establishment has occurred. This makes S100A9 a prime target in both prophylactic and therapeutic settings; yet, targeted immunotherapies against S100A9 have never previously been explored. CPMV has been shown in the past to be immunostimulatory when injected directly into the tumor with the ability to recruit immune cells for tumor cell killing. However, metastatic tumors cannot be treated through intratumoral injections; therefore, the current work utilizes systemically-administered S100A9-targeted CPMV nanoparticles. Biodistribution studies indicate that S100A9-targeted CPMV homes to the lung while confocal imaging of S100A9 and S100A9-targeted CPMV within the lungs of tumor-inoculated mice demonstrates co-localization. We further demonstrate using flow cytometry that after CPMV homes to the lungs, immune cells such as neutrophils and dendritic cells are recruited to the lungs, and macrophages are polarized towards their antitumor M1 phenotype. Prophylaxis efficacy studies where CPMV is injected before the tumors show that the S100A9-targeted CPMV causes tumor rejection in both metastatic breast cancer and melanoma but that native CPMV does not produce a significant effect. When used as a treatment, the targeted CPMV, similarly shows efficacy against these two cancer models with native CPMV again showing ineffectiveness. The S100A9-targeted CPMV holds great potential as a targeted immunotherapy both prophylactically (e.g. after primary tumor debulking to reduce the onset of metastases) and therapeutically after tumor establishment has occurred. Citation Format: Young Hun Chung, Jooneon Park, Hui Cai, Nicole F. Steinmetz. Prophylaxis and treatment of metastatic breast cancer and melanoma using S100A9-targeted cowpea mosaic virus nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 297.
Abstract 544: Role of an ankyrin domain protein in hepatocellular carcinoma progression
Authors: Samantha Lopez, Adithya Anilkumar, Kyle Doxtater, Sudhir Kotnala, Neeraj Chauhan, Murali Yallapu, Meena Jaggi, Subhash Chauhan, Manish Tripathi
Journal: Cancer Research (2022)

Abstract Background: Liver cancer is the third leading cause of mortality attributed to cancer. Hepatocellular carcinoma (HCC) is the most prevalent form among various histological types accounting for 85% to 90% of primary liver cancers. As per Texas Cancer Registry, the Hispanic population had an incidence of 21.2 per 100,000 in Texas. The Rio Grande Valley, located in South Texas, is an underserved area composed highly of Hispanics. It faces multiple disparities that can attribute to increased risk factors of HCC and, thus, a higher liver cancer incidence and mortality. Due to this, there is a need to identify a new, inexpensive, and faster diagnostic biomarker in liver cancer. We have recently identified an extracellular secreted cancer antigen POTE-2, a member of the ankyrin domain-containing POTE gene family. Our preliminary data indicates high POTE-2 expression in HCC tumors. In this study, we will discuss the role of POTE-2 in HCC progression and its associated regulatory pathways. Methods: The Cancer Genome Atlas (TCGA) database of HCC patients (n=371 tumor; n=50 normal) was analyzed. Liver cancer cell lines procured from ATCC were analyzed for POTE-2 mRNA and protein expression through RT-PCR and western blot, respectively. Lentiviral-based plasmids were used for overexpression and knockdown studies for oncogenic assays. Localization of POTE-2, YAP1, and PDL1 was identified with immunofluorescence. Results: Comprehensive analysis of the TCGA database showed increased POTE-2 expression in tumors and is upregulated in all stages of HCC. Lentiviral transduction led to a change in phenotype in oncogenic assays. Modulation of POTE-2 expression led to changes in kinase activity and regulatory pathways. Immunofluorescence showed nuclear localization of YAP1 and PDL1 in the liver cancer cell lines. Conclusion: These studies will help discover novel mechanisms of POTE-2 protein function, signaling pathways, and its role in liver cancer progression. Citation Format: Samantha Lopez, Adithya Anilkumar, Kyle Doxtater, Sudhir Kotnala, Neeraj Chauhan, Murali Yallapu, Meena Jaggi, Subhash Chauhan, Manish Tripathi. Role of an ankyrin domain protein in hepatocellular carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 544.
Abstract 5998: Peroxiredoxin IV promotes progression of colorectal cancer
Authors: Pratik Thapa, Hong Jiang, Yanning Hao, Na Ding, Aziza Alshahrani, Yekaterina Zaytseva, Qiou Wei
Journal: Cancer Research (2022)

Abstract Peroxiredoxin IV (Prx4) is a multifunction enzyme with a primary antioxidant role of reducing free radicals such as hydrogen peroxide and peroxynitrite. Literature review suggests that Prx4 upregulation in colorectal cancer is associated with higher tumor metastasis and shorter survival of patients. However, the function and mechanisms of Prx4 in cancer development are not well understood. The goal of this study is to validate the oncogenic role of Prx4 and to identify potential mechanisms of invasion and metastasis. Western Blot was performed to compare the expression of Prx4 protein in a normal colon cell line and seven colorectal cancer cell lines. shRNA mediated knockdown of Prx4 was performed in cancer cell lines with higher expression of Prx4. Stable vector control and Prx4 knockdown cells were used to perform Scratch Wound healing assay to compare the rate of migration. Transwell Matrigel invasion assay was performed using the same cell lines with 10% FBS containing-medium as chemoattractant. Vector control and Prx4 knockdown HCT116 cells were orthotopically implanted into the cecum wall of immunodeficient mice and humanely euthanized four weeks later. Prx4 expression is upregulated in colorectal cancer cell lines compared to normal colon cell line NCM356. Stable knockdown of Prx4 in HCT116 and RKO cell lines resulted in a significant decrease in migration and invasion rates of cancer cell lines in vitro compared to vector control. Orthotopic implantation of HCT116 vector control and Prx4 knockdown cells into cecum wall resulted in a lower metastasis rate to the liver and the lungs. We are currently conducting mechanistic studies to determine how the loss of Prx4 leads to a decrease in malignancy of colorectal cancer cell lines. Prx4 promotes colorectal cancer cell invasion and metastasis. Our study suggests Prx4 is a critical oncogenic protein that can be used as a therapeutic target for patients. This work was partially supported by the National Institutes of Health R01CA222596, Molecular Mechanisms of Toxicity Training Grant in Toxicology (T32ES07266), and American Cancer Society RSG-16-213-01-TBE. Citation Format: Pratik Thapa, Hong Jiang, Yanning Hao, Na Ding, Aziza Alshahrani, Yekaterina Zaytseva, Qiou Wei. Peroxiredoxin IV promotes progression of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5998.
Abstract 1330: Role of ENPP1 mediated extracellular cGAMP hydrolysis in cancer metastasis and immune evasion
Authors: John Young Ho Kwon, Jun Li, Mercedes Duran, Ninjit Dhanota, Samuel Bakhoum
Journal: Cancer Research (2022)

Abstract Chromosome instability (CIN) promotes metastasis through sustained tumor-cell autonomous response to cytosolic DNA. Chromosome mis-segregation engenders the formation of micronuclei, which upon rupture chronically activates the cGAS-STING DNA sensing pathway. Tumor cGAS recognizes cytosolic DNA to generate cGAMP, a potent immune-stimulatory molecule that is readily exported into the extracellular space to enforce a type 1 IFN-mediated anti-tumor response in a host STING dependent manner. However, it is unclear how highly aggressive, unstable tumors have evolved to co-opt this chronic inflammatory signaling to drive tumorigenic behaviors and immune evasion. Here, we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) may drive tumor metastasis through degradation of extracellular cGAMP. Using RNA sequencing of isogenic tumors, we uncovered a link between ENPP1 and CIN. We leveraged syngeneic mouse models to demonstrate that genetic perturbation of tumor ENPP1 and overexpression of a catalytically inactive ENPP1 mutant suppress metastasis. Furthermore, loss of ENPP1 increases tumor immune infiltration, reduces extracellular adenosine, and enhances response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. In line with these findings, ENPP1 expression correlates with immune suppression in human cancers. These results suggest that ENPP1-mediated hydrolysis of cGAMP may facilitate metastasis through evasion of immune surveillance, perhaps in part through cGAMP breakdown into immune-suppressive adenosine, in which the contributions of tumor and host adenosine can be further explored. Taken together, our study demonstrates how ENPP1-mediated hydrolysis of cGAMP can transform an otherwise inflammatory pathway into an immune-suppressive mechanism to promote tumor progression and metastasis. Citation Format: John Young Ho Kwon, Jun Li, Mercedes Duran, Ninjit Dhanota, Samuel Bakhoum. Role of ENPP1 mediated extracellular cGAMP hydrolysis in cancer metastasis and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1330.
Abstract 5587: STING and TLR 7/8 Agonist combination can improve immune checkpoint blockade therapy efficiency
Authors: Vishnu Revuri, Shubhmita Bhatnagar, John Schultz, Peter Larson, David M. Ferguson, Jayanth Panyam
Journal: Cancer Research (2022)

Abstract Despite significant advancements in immune checkpoint blockade (ICB) therapy, only few patients respond to the treatment. Non-immunogenic cold tumors lack T-cell infiltration, which results in reduced ICB therapeutic efficiency. Immune adjuvants can reprogram the non-immunogenic cold tumor microenvironment (TME) to inflamed hot TME by activating antigen presenting cells and improving T-cell homing. Here, we investigate the potentials of 558 (a novel TLR 7/8 agonist) and ADU-S100 (stimulator of interferon gene (STING) agonist in clinical trials) combination on improving the activity of ICB. Human TLR-specific reporter cell assay using HEK-Blue™-hTLR7 and 8, confirmed the activation of both TLR 7 and TLR 8 with EC50 of 0.18 µM and 5.34 µM respectively, when treated with 558. In addition, treatment of human PBMCs with 558 increased the IFN-γ and TNF-α cytokine secretions. Moreover, the levels of IL-10, an anti-inflammatory cytokine were not increased upon treatment with 558. Although treatment of bone marrow derived dendritic cells (BMDC) with 558 resulted in CD40 expression, a reduced expression of CD80 and CD86, costimulatory molecules that are required for T-cell activation, was observed. Interestingly, 558 in combination with ADU-S100 not only increased the CD40 expression but also improved the expression of CD80 (4-fold) and CD86 on BMDCs. Furthermore, the levels of pro-inflammatory cytokines TNF-α and IL-6 was significantly increased when BMDCs were treated with 558 and ADU-S100 combination compared to the individual treatments. TME constitute M2 polarized macrophages that promote secretion of anti-inflammatory cytokines and favor tumor progression. Interestingly, 558 and ADU-S100 combination reduced the expression of CD206, a mannose receptor that is highly expressed on M2 macrophages and improved the expression of CD80 (25-fold) and CD86 (6-fold) compared to 558 treatments alone. These results confirmed the polarization of M2 macrophages to immunogenic M1 macrophages. Overall, these studies indicate promising potential of 558 and ADU-S100 combination in reprogramming the TME to aid in effective cancer treatments. Citation Format: Vishnu Revuri, Shubhmita Bhatnagar, John Schultz, Peter Larson, David M. Ferguson, Jayanth Panyam. STING and TLR 7/8 Agonist combination can improve immune checkpoint blockade therapy efficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5587.